Predictive and prognostic role of protease-activated receptors (PARs) in colorectal cancer (CRC).

Abstract

213 Background: Protease-activated receptors (PARs) are G-protein-coupled receptors activated by thrombin and tissue factor (TF)-VIIa complexes. In colorectal cancer (CRC), TF promotes thrombosis, tumor progression, and therapy resistance in part through PAR signaling. We evaluated expression of F2R (PAR-1), F2RL1 (PAR-2), F2RL2 (PAR-3), and F2RL3 (PAR-4) and their associations with prognosis and treatment outcomes in CRC. Methods: PAR gene expression was analyzed using data from 433 metastatic CRC patients in CALGB/SWOG (Alliance) 80405 who received first-line chemotherapy with either bevacizumab (n = 226) or cetuximab (n = 207). RNA was extracted from FFPE tumor samples and sequenced on the HiSeq 2500 platform (Illumina). Patients were stratified into tertiles or quartiles by gene expression. Overall survival (OS) and progression-free survival (PFS) were compared using multivariate Cox models adjusted for age, sex, ethnicity, ECOG status, tumor location, number of metastatic sites, KRAS/MSI status, and treatment arm. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were reported. Log-rank p-values were used for unadjusted comparisons. Fisher’s exact and chi-square tests assessed categorical associations; FDR-adjusted significance was defined as Q < 0.05. Results: High PAR-3 expression was associated with improved OS (35.9 vs. 24.9 months; HR 0.80, 95% CI 0.72–0.90; p = 2e-04, FDR < 0.05). A survival benefit was also seen with chemotherapy plus bevacizumab (36.1 vs. 25.2 months; HR 0.81, 95% CI 0.70–0.94; p = 0.0059) and trended toward improved OS with cetuximab (35.8 vs. 22.1 months; HR 0.82, 95% CI 0.67–1.00; p = 0.051). High PAR-1 expression was associated with inferior PFS (10.0 vs. 11.9 months; HR 1.15, 95% CI 1.03–1.29; p = 0.014) and trended toward worse OS (26.5 vs. 35.8 months; HR 1.11, 95% CI 0.98–1.25; p = 0.091). This effect was particularly evident with chemotherapy plus cetuximab (26.0 vs. 37.1 months; HR 1.38, 95% CI 1.12–1.68; p = 0.0019). High PAR-4 expression trended toward worse PFS (10.2 vs. 11.3 months; HR 1.10, 95% CI 1.00–1.21; p = 0.058) and OS (27.7 vs. 30.7 months; HR 1.11, 95% CI 0.99–1.24; p = 0.061). High PAR-2 expression was not significantly associated with OS (29.0 vs. 29.4 months; HR 0.93, 95% CI 0.84–1.04; p = 0.23). Conclusions: High PAR-3 expression was associated with significantly prolonged OS and may serve as an independent prognostic biomarker in CRC. Associations with improved outcomes with bevacizumab suggest a potential link between PAR-3 signaling and angiogenic pathways. In contrast, high PAR-1 expression correlated with inferior PFS and significantly worse outcomes with cetuximab, potentially reflecting interaction with mechanisms of EGFR resistance. These findings support further investigation of TF-PAR signaling in CRC to clarify these mechanisms and assess their therapeutic implications.